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Complex folding pathways in a simple β‐hairpin
Author(s) -
Wei Guanghong,
Mousseau Normand,
Derreumaux Philippe
Publication year - 2004
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.20127
Subject(s) - protein folding , downhill folding , reptation , molecular dynamics , folding (dsp implementation) , lattice protein , hydrogen bond , chemical physics , chemistry , statistical physics , molecular biophysics , computational chemistry , physics , biological system , phi value analysis , molecule , biology , quantum mechanics , biochemistry , organic chemistry , electrical engineering , engineering , polymer
The determination of the folding mechanisms of proteins is critical to understand the topological change that can propagate Alzheimer and Creutzfeld‐Jakobs diseases, among others. The computational community has paid considerable attention to this problem; however, the associated time scale, typically on the order of milliseconds or more, represents a formidable challenge. Ab initio protein folding from long molecular dynamics simulations or ensemble dynamics is not feasible with ordinary computing facilities and new techniques must be introduced. Here we present a detailed study of the folding of a 16‐residue β‐hairpin, described by a generic energy model and using the activation‐relaxation technique. From a total of 90 trajectories at 300 K, three folding pathways emerge. All involve a simultaneous optimization of the complete hydrophobic and hydrogen bonding interactions. The first two pathways follow closely those observed by previous theoretical studies (folding starting at the turn or by interactions between the termini). The third pathway, never observed by previous all‐atom folding, unfolding, and equilibrium simulations, can be described as a reptation move of one strand of the β‐sheet with respect to the other. This reptation move indicates that non‐native interactions can play a dominant role in the folding of secondary structures. Furthermore, such a mechanism mediated by non‐native hydrogen bonds is not available for study by unfolding and Gō model simulations. The exact folding path followed by a given β‐hairpin is likely to be influenced by its sequence and the solvent conditions. Taken together, these results point to a more complex folding picture than expected for a simple β‐hairpin. Proteins 2004;9999:000–000. © 2004 Wiley‐Liss, Inc.